Matt Hoffman, Senior Editor for NeurologyLive, has covered medical news for MJH Life Sciences, NeurologyLive’s parent company, since 2017. He hosts the NeurologyLive 

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 suggests that the slowing of heart rate experienced by individuals after seizure during sleep, secondary to the synergistic effects of non-rapid eye movement (REM) sleep on parasympathetic tone, may play a role in the increased risk of sudden unexpected death in epilepsy (SUDEP) during sleep.

The work included a group of 42 individuals (mean age, 40.5 years [±14.6]; average duration of diagnosis, 20.5 years [±16.9]) in the University of Virginia epilepsy monitoring unit with electroencephalographically confirmed events totaling 101 seizures between February 2018 and August 2019. The individuals included were on a variety of antiepileptic medicines and experienced focal, generalized, and undetermined onset seizures (

). Heart rate data was acquired prospectively.

Ultimately, the depth of sleep during the 5 minutes prior to seizure correlated with the postictal nadir heart rate (PINHR; correlation coefficient [CC], –.299; 

 <.05), and the relationship was more significant when adjusted for age, generalized tonic-clonic seizures, and baseline heart rate (CC, −.272 [95% CI, −.392 to −.152]; 

 <.001). The group concluded that sleep depth is an independent predictor of the change in heart rate following a seizure.

“We have been trying to better understand the cardiac changes around the time of a seizure in patients with epilepsy. When we looked at the heart rates for patients with epilepsy admitted to the hospital, many of them develop tachycardia following a seizure, but a subset of patients have a decreased heart rate. This decline was more pronounced when the patients were asleep,” said lead author Andrew Schomer, MD, assistant professor, Department of Neurology and UVA Brain Institute, University of Virginia Health, in a statement.

“The mechanism of SUDEP, or sudden unexpected death in epilepsy, is still not fully understood. We know there is an increased risk during sleep and if seizures are poorly controlled. Hopefully, with further study we can try to identify individuals who are at an increased risk and work to prevent this devastating outcome,” Schomer continued.

The group utilized sleep depth as the main independent variable, with it being defined as the weighted sum of the preictal 5 minutes or 10 epochs (wake = 0 points; N1 = 1 point; N2 = 2 points; N3 = 3 points), meaning sleep depth could range from 0 to 30 points, with 30 implying all epochs were N3 sleep. According to Schomer et al, “only a few epochs preceding seizures consisted of REM sleep, so it was excluded from sleep depth calculation.”

Epilepsy Foundation and Eisai Partner to Develop EDEN Patient Platform

In total, 35% (n = 35) of the seizures were preceded by at least 1 epoch of sleep, with the average sleep depth of patients 5 minutes prior to seizure was 4 (±7.2). The recorded PINHR for all seizures was between 43 and 188 beats per minute (mean, 71.1 [±12.4]).

“People with poorly controlled seizures have the greatest risk of SUDEP, and seizures during sleep may hold the higher risk,” said Mark Quigg, MD, MSc, professor, Department of Neurology and UVA Brain Institute, University of Virginia Health, in a statement.

 “Our findings can direct further research to determine how the heart’s and lung’s control systems fail during sleep-related seizures in order to help prevent SUDEP.”

This is not the first research to assess the relationship between sleep and seizure or SUDEP, nor with the latter and heart rate. Recently 

suggest that most patients with subsequent SUDEP experienced an abnormal cardiac autonomic response to sympathetic stimulation by hyperventilation. Those investigators, led by William Szurhaj, MD, PhD, conducted a retrospective, observational, case-control study of a group of 20 patients who died from SUDEP and 20 matched controls.

Szurhaj et al observed that in patients who died from SUDEP, heart rate and root mean square of successive differences between normal heartbeats (RMSSD) did not change significantly during or after hyperventilation. A difference in heart rate between the end of the hyperventilation and 4 minutes after its end discriminated between SUDEP patients and control patients with an area under the curve of (AUC) of 0.870, a sensitivity of 85%, and a specificity of 75%.

presented at the 2020 American Epilepsy Society (AES) Annual Meeting

 suggest that REM sleep onset seizures did not correlate with the incidence of SUDEP.

 Those data, presented by Michael Sperling, MD, included a cohort of 26 patients who died of SUDEP, a group in which the frequency of seizures arising from REM sleep was 1.9% (2 of 107), comparable to the 1% frequency that had previously been reported. Despite the low percentage of total seizures arising from REM, 2 patients (7.7%) recorded REM-onset seizures, and both experienced a single seizure arising from REM sleep and additional seizures arising from other states of sleep.

All told, the data on the percentage of patients with seizures arising from each vigilance state showed that 42% of seizures were during sleep and wakefulness, 31% during wakefulness only, 19% during sleep only, and 8% of patients had no seizures recorded. In total, 22 (85%) patients had a history of tonic-clonic seizures, and 22 (85%) with a history of nocturnal seizures. The mean number of seizures per patient was 4.1 (range, 0–13) among a total cohort of 107 seizures recorded.

Another presentation at AES 2020 found the 

 than what was previously reported. The overall rate of mortality was 0.26 per 100,000 infants and children compared to literature which has suggested that the mortality rate is 0.16 per 100,000 infants and children. Additionally, the data from the National Institutes of Health (NIH) and Centers for Disease Control and Prevention (CDC) Sudden Death in the Young (SDY) Case Registry revealed that black and multiracial infants and children (38%; 0.32 per 100,000) have a SUDEP mortality rate 1.5 times higher than white infants and children (58%; 0.22 per 100,000).

REFERENCES
1. Schomer AC, Lynch M, Lowenhaupt S, et al. Synergistic effect of sleep depth and seizures correlates with postictal heart rate. 

. 2021;61(5):e65-e69. doi:10.1111/epi.16869
2. Epilepsy Research Reveals Why Sleep Increases Risk of Sudden Death. News release. May 5, 2021. Accessed May 11, 2021. https://www.newswise.com/articles/epilepsy-research-reveals-why-sleep-increases-risk-of-sudden-death
3. Szurhaj W, Leclancher A, Nica A, et al. Cardiac autonomic dysfunction and risk of sudden unexpected death in epilepsy. 

Published online April 9, 2021. doi: 10.1212/WNL.0000000000011998
4. Goldstein L, Resekhi RT, Sperling M, Nei M. The prevalence of REM sleep onset seizures in a cohort of patients who died of SUDEP. Presented at AES 2020 Virtual Meeting: December 4–8, 2020. Abstract 258.
5. Whittmore V, Burns KM, Shaw E, Faulkner M, Tian N. Population-based surveillance of sudden unexpected death in epilepsy using the sudden death in the young case registry. Presented at AES 2020 Virtual Meeting: December 4–8, 2020. Abstract 405.

Articles

Sleep depth was observed to be an independent predictor of heart rate change following seizure for patients with epilepsy.

Non-REM Bradycardia and Sleep Seizures May Increase Risk of SUDEP

A recently published study’s findings suggest that the improvements in disease-modifying therapeutics (DMTs) and management standards have led to the reduction of the risk of persistent disability for individuals with pediatric-onset multiple sclerosis (MS) by 50% to 70%. The results imply that an increase in approved DMTs prior to age 18 and continuous upgrades to management tactics can further advance prognosis for this patient population.

In a cohort of more than 3100 patients with pediatric-onset disease, the cumulative risk of reaching disability milestones decreased gradually over time for Expanded Disability Status Scale (EDSS) scores of both 4.0— implying significant disability but self-sufficiency and an ability to be up and about for about 12 hours per day— and 6.0—implying the requirement of a walking aid such as a cane or crutch. The hazard ratios (HRs) of these milestones were compared between pre-1993 and the time periods of 1993-1999, 2000-2006, and 2007-2013.

“The gradual decrease of disability risk corresponded to an increased use of DMTs over time, especially the most efficacious (ie, natalizumab and fingolimod), while disease activity at onset did not change significantly. Moreover, in recent diagnosis epochs, patients with [pediatric-onset] MS started earlier and continued taking DMTs longer compared with the past,” the study authors, including Pietro Iaffaldano, MD, assistant professor of neurology, University of Bari Aldo Moro, concluded. “Based on these results, our hypothesis is that improvement of [pediatric-onset] MS prognosis probably depends on changing therapeutic standards in MS.”

Iaddaldano and colleagues added that patients with pediatric diagnosis (n = 1300; 41% of the total cohort), who were the most active and early treated, had a lower HR for reaching EDSS of at least 4.0 in the most recent diagnosis epoch of 2007-2013 (HR, 0.35; 95% CI, 0.19-0.63). 

All told, though, the median survival time to reach EDSS of at least 4.0 and at least 6.0 was lower for patients with pediatric diagnosis (EDSS 4.0: 27.8 years [95% CI, 25.7-29.8]; EDSS 6.0: 35.2 years [95% CI, 31.7-38.6]) than those with adult diagnosis (EDSS 4.0: 32.8 years [95% CI, 31.7-33.8]; EDSS 6.0: 41.1 years [95% CI, 38.8-43.2]), a difference which was statistically significant (

Targeting Chronic Inflammation in Progressive MS

“Similar to the overall cohort, the risk of reaching disability milestones decreased over time for EDSS scores of at least 4.0 in the adjusted Cox model. However, for EDSS scores of at least 6.0, the latest diagnosis epoch (2007-2013) did not reach statistical significance, but the number of events was very low,” Iaddaldano et al. wrote.

The percentage of patients starting DMTs in pediatric age was higher than the rest of the cohort (53% vs 1%; 

 < .001), and it significantly increased over time (12%, 32%, 66%, and 79% in <1993, 1993-1999, 2000-2006, and 2007-2013, respectively; 

The full study cohort included 3198 patients (69% female) with a mean age of disease onset of 15.2 years and a median time to diagnosis of 3.2 years, and a mean follow-up of 21.8 years (standard deviation [SD], 11.7). The annualized relapse rate (ARR) in the first year was 1.3 and in the first 3 years was 0.6, and median survival times to reach EDSS score of 4.0 and 6.0 were 31.7 years (95% CI, 30.6-32.7) and 40.5 years (95% CI, 38.6-42.4), respectively.

The distribution of patients among the assessed diagnosis epochs was 259 (20%) pre-1993, 259 (20%) from 1993-1999, 368 (28%) from 2000 to 2006, and 414 (32%) from 2007 to 2013. Data were extracted and collected in May 2019 from the Italian MS Registry, a digital database including more than 59 000 patients.

The cumulative risk of reaching disability milestones gradually decreased for EDSS with the following HRs for the 3 comparative time periods:

“In later diagnosis epochs, a greater number of patients with [pediatric-onset] MS were treated with DMTs, especially high-potency drugs, that were given earlier and for a longer period. Demographic characteristics and clinical disease activity at onset did not change significantly over time,” Iaffaldano et al. wrote.

REFERENCE
Baroncini D, Simon M, Iaffaldano P, et al. Risk of Persistent Disability in Patients With Pediatric-Onset Multiple Sclerosis. 

. Published online May 3, 2021. doi:10.1001/jamaneurol.2021.1008.

Improvements in DMTs and management standards appear to have lowered the risk of progression to EDSS scores of 4.0 and 6.0 for those with pediatric-onset disease.

Treatment Improvements for Pediatric-Onset MS Have Reduced Risk of Persistent Disability

The Epilepsy Foundation announced this week that it has entered into a collaboration with Eisai to develop a novel platform for individuals with epilepsy, dubbed EDEN (Epilepsy Digital Experience Navigator).

The aim, according to the foundation’s announcement, is to provide these patients, their caregivers, and their clinicians with an improved method of data utilization for a smoother journey with the disease. The Epilepsy Foundation stated that it plans to have EDEN up and running by the fall of this year.

The EDEN platform is anticipated to enable those with epilepsy to easily connect to their care, as well as have access to resources and information that is individualized to their experience. The platform will both collect and analyze patient medical records, survey responses, and data from connected devices to develop real-world insights for clinical research in the effort to manufacture novel treatments, innovations, and means to the epilepsy community.

"The Epilepsy Foundation is committed to shaping the future of epilepsy research and leveraging technology to create greater efficiency in epilepsy care and treatment," said Jacqueline French, MD, chief medical and innovation officer, Epilepsy Foundation, in a statement. "Getting the right information to the right person at the right time is critical for successfully managing epilepsy. Our collaboration with Eisai empowers people with epilepsy to successfully manage their condition while contributing to research that we hope can help improve standards of care in the future for people living with epilepsy."

French, who is also director of Translational Research and Clinical Trials in Epilepsy at NYU Grossman School of Medicine, recently spoke with 

 about the importance of improving not only the standards of care for individuals with epilepsy but the recognition of the condition of epilepsy in general, which occurs in 1 of every 28 individuals. She specifically spoke to findings of a recent study she conducted and the 5 S’s—

pells—that can help potentially identify nonmotor seizures. She clarified that for physicians, it is important to note that if a convulsion is reported, that inquiring about additional spells is critically important.

Abnormal Cardiac Autonomic Response Observed Prior to SUDEP

Treatment and diagnosis delays have been a longstanding challenge for epileptologists. At the 

2021 American Academy of Neurology Annual Meeting

, April 17-22, Joseph Sirven, MD, and colleagues presented a study that evaluated the role of social determinants in these delays for Arizonans on Medicaid. They found that individuals with epilepsy diagnosed in inpatient settings or emergency departments had 2 times or 1.4 times, respectively, higher odds of being treated within 30 days compared to those diagnosed in office/clinic settings. Additionally, they found that factors such as care setting, age, marital status, race, homelessness, and employment all played significant roles that correlated with treatment delays. They wrote that these results underscore the need for a deeper understanding of the complex interplay of social determinants of health factors on epilepsy care, which to this point has been relatively under-researched.

EDEN is planned to be powered by the technology platform developed by Embleema, a regulatory-grade health data platform that utilizes blockchain. Embleema will capture the clinical and real-world data, driven by patients, and according to the announcement “continuously delivers insights to multiple care and research stakeholders,” which may help to improve outcomes by streamlining the data interpretation process. Robert Chu, chief executive officer, Embleema, noted in a statement that the company was “delighted” to be part of the collaboration.

"For the first time, patients will be able to directly contribute to research by continuously sharing rich real-world insights with stakeholders in a fully remote and consented manner, while at the same time benefit from personalized digital services to better manage their condition," Chu said.

According to Embleema, providing those with epilepsy a way to stay on top of their disease both at home and on their mobile devices. The company noted that it prioritizes patient needs first, aiming for them to be “an equal voice in research” and able to receive multiple benefits from that research. EDEN, it notes on its website, was designed and developed fully based on patient feedback to build a system around those who will use it and derive the benefit from it.

"At Eisai, everything we do is guided by our Human Healthcare mission, putting patients and their families first while we also listen and learn from them. We seek to enable people to live their fullest lives and continue to pursue the creation of solutions based on scientific evidence to help them achieve this," said Ivan Cheung, chairman, and global president, Neurology Business Group, Eisai, in a statement. "Partnering with the Epilepsy Foundation on the launch of EDEN continues our commitment to patients and families in the epilepsy community, as we together pursue and advance new epilepsy solutions."

REFERENCES
1. Epilepsy Foundation Collaborates with Eisai to Develop Epilepsy Digital Experience Navigator. News release. May 4, 2021. Accessed May 7, 2021. https://www.prnewswire.com/news-releases/epilepsy-foundation-collaborates-with-eisai-to-develop-epilepsy-digital-experience-navigator-301282981.html
2. Pellinen J, Tafuro E, Yang A, et al. Focal nonmotor versus motor seizures: The impact on diagnostic delay in focal epilepsy. 

. Published online October 20, 2020. doi:10.1111/epi.16707
3. Sirven J, Sprout G, Speer M, Simic G, Reddy S. The role of social determinants in epilepsy treatment delays for Arizonans on Medicaid. Presented at American Academy of Neurology Annual Meeting; April 17-22. Abstract P11.008
4. EDEN. Ebleema website. Updated 2021. Accessed May 7, 2021.https://embleema.com/ed

The Epilepsy Digital Experience Navigator, or EDEN, platform, is being developed in tandem with Embleema, with an aim of improving data use and collection for individuals with epilepsy.

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Matt Hoffman

Articles

Non-REM Bradycardia and Sleep Seizures May Increase Risk of SUDEP

Treatment Improvements for Pediatric-Onset MS Have Reduced Risk of Persistent Disability

Epilepsy Foundation and Eisai Partner to Develop EDEN Patient Platform

Episode 36: Zavegepant and the Gepant Class for Migraine Care